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Taking Research and Development to the Clinic: Issues for Physicians. AAAS/FDLI Colloquium I Diagnostics and Diagnoses Paths to Personalized Medicine Howard Levy, MD, PhD Johns Hopkins University June 1, 2009. What is Personalized Medicine?. Biomarkers and genetic tests

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taking research and development to the clinic issues for physicians

Taking Research and Development to the Clinic: Issues for Physicians

AAAS/FDLI Colloquium I

Diagnostics and Diagnoses

Paths to Personalized Medicine

Howard Levy, MD, PhD

Johns Hopkins University

June 1, 2009

what is personalized medicine
What is Personalized Medicine?
  • Biomarkers and genetic tests
  • Customization of medical care to the individual patient
  • All aspects of care—not just biomarkers, not just genetics
challenges opportunities
Challenges & Opportunities

Self-evident truths:

  • Physicians want to help patients
  • Time & resources are scarce

Can biomarkers improve both?

using a biomarker
Select a test

Order a test

Get it paid for

Get it done

Receive result

Understand result

Archive result

Access result

(now & future)

Apply result in clinical care

Using a Biomarker
clinical utility
Clinical Utility

Does the biomarker improve clinical care?

  • Pharmacogenetics
  • Predictive testing
  • Faster or more precise diagnostics
clinical utility1
Clinical Utility

What are the costs?

  • Financial
  • Time/Resources
  • Social/Ethical/Legal
  • Medical (incorrect conclusions)
  • Psychological
pharmacogenetics
The right drug

At the right time

In the right dose

↑ Efficacy

↓ Adverse events

Pharmacogenetics
warfarin dosing
Warfarin Dosing
  • Fixed-dose
  • Clinical algorithm (weight, age, sex)
    • This is personalized medicine!
  • Pharmacogenetic (VKORC1 & CYP2C9)
    • PGx explains ~40% of dose variability
    • Clinical + PGx explains ~54% of variability
int l warfarin pgx consortium
Int’l Warfarin PGx Consortium

N Engl J Med

360(8):753-764

February 19, 2009

warfarin pgx clinical utility
Warfarin PGx Clinical Utility
  • Likely to achieve therapeutic dose faster
  • Relatively easy to order & receive results
  • Often covered by 3rd parties
  • Algorithm freely available
  • Improved efficacy & fewer adverse events?
    • Seems likely
    • Still being studied
warfarin pgx clinical utility1
Warfarin PGx Clinical Utility

Limitations:

  • Needs to be done promptly at initiation of therapy
  • ~45% of dose variability unexplained
  • Environmental factors remain important
drug metabolism cyp450
Drug Metabolism: CYP450
  • >50% of all drugs
  • Prodrug  Active Drug
  • Active  Inactive
  • Relevant Factors:
    • Other drugs
    • Diet & environment
    • Genetic variants
cyp450 pgx clinical utility
CYP450 PGx Clinical Utility
  • Genetic testing is available
  • Is PGx testing better than trial & error?
  • Drug choice & dosing recommendations?
  • What if there are no alternatives?
    • Psychological distress
    • Relative risk
    • Genetic determinism
genetic determinism
Genetic Determinism

Belief that clinical outcomes are inexorably defined by genetic factors

Ignores:

  • Genetic/epigenetic modifiers
  • Environmental modifiers
  • Variable expression
  • Reduced penetrance
predictive testing
Predictive Testing

“It’s tough to make predictions, especially about the future”

-Dan Quayle, Casey Stengel, et al.

“The future ain’t what it used to be”

-Yogi Berra

genetic risk assessment
Genetic Risk Assessment
  • Family History
    • Varies over time
  • DNA variants
    • Stable over time
    • Relative risk
gwas genome wide association studies
GWAS: Genome-Wide Association Studies
  • Really BIG case-control study
    • 1000’s of subjects
    • 500,000 to 1,000,000 SNPs
  • Power to detect small effect sizes
  • Subject to same errors & biases as any other epidemiologic study
cad risk assessment gene environment
CAD Risk Assessment:Gene ↔ Environment
  • Smoking, HTN, DM, etc: OR ≈ 10-20
  • SNPs: OR ≈ 1.2-2.0 (usually 1.2-1.3)
  • Family History: intermediate
heritability
Heritability
  • Proportion of disease predispositionthat is due to inherited factors
    • SNPs—small amount
    • Other heritable factors

(DNA & Non-DNA variants)

  • Current tests assess only a small portion of heritability
analytical clinical validity
Analytical & Clinical Validity
  • Is the test accurate?
  • Does the biomarker correlate clinically (retrospective vs. prospective study)?
  • How are results of multiple tests combined?
  • Validity is often assumed when test is offered clinically.
the fallacy of genetic determinism
The Fallacy of Genetic Determinism

Positive tests ≠ Disease

Negative tests ≠ Health

clinical utility of genetic testing for common disease
Clinical Utility of Genetic Testing for Common Disease?
  • What do the results mean?
  • Small effect size
  • Environmental factors
  • Fallacy of genetic determinism
  • Undue anxiety/false reassurance?
clinical utility of genetic testing for common disease1
Clinical Utility of Genetic Testing for Common Disease?
  • Modify therapy to reduce risk?
  • Motivation to change behavior?
    • Smoking, exercise & diet campaigns
    • Does the Personalized Medicine model work?
clinical utility of genetic testing for common disease2
Clinical Utility of Genetic Testing for Common Disease?
  • Cost
  • Large amounts of clinical data
  • Paucity of tools to integrate data
  • Uncertain plan of action
  • May be appropriate for some patients
pm opportunities
PM Opportunities
  • Improved diagnostics
  • Improved therapeutics
  • Improved health maintenance
  • More efficient use of time
  • Lower health care costs
  • Patient & physician satisfaction
pm challenges
PM Challenges

Clinician Education

  • Test indications
  • Test validity
  • Result interpretation
  • Clinical utility
  • Integration into clinical care
clinician education
Clinician Education

Learning Preferences

  • Clinically relevant
  • Just in time (point of care)
  • Fast (<2 minutes)
  • Increasingly Internet-based
  • 2o sources (authority vs. accuracy)
  • GeneFacts
pm challenges1
PM Challenges

Test Validity

  • Transparency
    • Providers lack time & knowledge to evaluate
  • Regulation
    • Slows progress, limits access, ↑ cost
  • Paternalism vs. Autonomy
pm challenges2
PM Challenges

Test Ordering & Payment

  • Facilitating ordering the correct test
  • DTC testing vs. physician gatekeeper
  • 3rd party payers
  • Paternalism vs. Autonomy
pm challenges3
PM Challenges

Receiving, Archiving and Accessing Results

  • EHRs
    • Can also prompt provider to order/use tests
  • PHRs
  • Information sharing between providers
    • Does the data already exist?
  • Privacy & Security
pm challenges4
PM Challenges

Clinical Utility

  • Better assessment of health factors
    • Genetic
    • Environmental
  • Better tools to combine environment, family history & biomarkers
  • Studies of actual clinical outcomes (Hype  Hope  Reality)
the art of medicine
The Art of Medicine
  • Evidence-based medicine
    • Based on population studies
  • Individual people
    • Autonomous
    • Variably reliable
    • Ever-changing environment
  • Personalized Medicine
    • Requires knowing & monitoring the patient and therapy at the individual level